S. Murray Sherman

Tonic and burst firing: dual modes of thalamocortical relay

All thalamic relay cells exhibit two distinct response modes--tonic and burst--that reflect the status of a voltage-dependent, intrinsic membrane conductance. Both response modes efficiently relay information to the cortex in behaving animals, but have markedly different consequences for information processing. The lateral geniculate nucleus, which is the thalamic relay of retinal information to cortex, provides a reasonable model for all of thalamus. Compared with burst mode, geniculate relay cells that are firing in tonic mode exhibit better linear summation, but have poorer detectability for visual stimuli. The switch between the response modes can be controlled by nonretinal, modulatory afferents to these cells, such as the feedback pathway from cortex. This allows the thalamus to provide a dynamic relay that affects the nature and format of information that reaches the cortex.

Thalamic relay functions and their role in corticocortical communication: generalizations from the visual system.

All neocortical areas receive thalamic inputs. Some thalamocortical pathways relay information from ascending pathways (first order thalamic relays) and others relay information from other cortical areas (higher order thalamic relays), thus serving a role in corticocortical communication. Most, possibly all, afferents reaching thalamus, ascending and cortical, are branches of axons that innervate lower (motor) centers, so that thalamocortical pathways can be viewed generally as monitors of ongoing motor instructions. In terms of numbers, the thalamic relay is dominated by synapses that modulate the relay functions. One of the roles of these modulatory pathways is to change the transfer of information through the thalamus, in accord with current attentional demands. Other roles remain to be explored. These modulatory functions can be expected to act on corticocortical communication in addition to their action on ascending pathways.

THE THALAMUS IS MORE THAN JUST A RELAY

The lateral geniculate nucleus and pulvinar are examples of two different types of relay: the former is a first order relay, transmitting information from a subcortical source (retina), while the latter is mostly a higher order relay, transmitting information from layer 5 of one cortical area to another cortical area. First and higher order thalamic relays can also be recognized for much of the rest of thalamus, and most of thalamus seems to be comprised of higher order relays. Higher order relays seem especially important to general corticocortical communication, and this challenges and extends the conventional view that such communication is based on direct corticocortical connections.

Thalamic relays and cortical functioning

Studies on the visual thalamic relays, the lateral geniculate nucleus and pulvinar, provide three key properties that have dramatically changed the view that the thalamus serves as a simple relay to get information from subcortical sites to cortex. First, the retinal input, although a small minority (7%) in terms of numbers of synapses onto geniculate relay cells, dominates receptive field properties of these relay cells and strongly drives them; 93% of input thus is nonretinal and modulates the relay in dynamic and important ways related to behavioral state, including attention. We call the retinal input the driver input and the nonretinal, modulator input, and their unique morphological and functional differences allow us to recognize driver and modulator input to many other thalamic relays. Second, much of the modulation is related to control of a voltage-gated, low threshold Ca(2+) conductance that determines response properties of relay cells -burst or tonic - and this, among other things, affects the salience of information relayed. Third, the lateral geniculate nucleus and pulvinar (a massive but generally mysterious and ignored thalamic relay), are examples of two different types of relay: the LGN is a first order relay, transmitting information from a subcortical driver source (retina), while the pulvinar is mostly a higher order relay, transmitting information from a driver source emanating from layer 5 of one cortical area to another area. Higher order relays seem especially important to general corticocortical communication, and this view challenges the conventional dogma that such communication is based on direct corticocortical connections. In this sense, any new information reaching a cortical area, whether from a subcortical source or another cortical area, benefits from a thalamic relay. Other examples of first and higher order relays also exist, and generally higher order relays represent the majority of thalamus. A final property of interest emphasized in chapter 17 by Guillery (2005) is that most or all driver inputs to thalamus, whether from a subcortical source or from layer 5 of cortex, are axons that branch, with the extrathalamic branch innervating a motor or premotor region in the brainstem, or in some cases, spinal cord. This suggests that actual information relayed by thalamus to cortex is actually a copy of motor instructions (Guillery, 2005). Overall, these features of thalamic relays indicate that the thalamus not only provides a behaviorally relevant, dynamic control over the nature of information relayed, it also plays a key role in basic corticocortical communication.

The corticothalamocortical circuit drives higher-order cortex in the mouse.

An unresolved question in neuroscience relates to the extent to which corticothalamocortical circuits emanating from layer 5B are involved in information transfer through the cortical hierarchy. Using a new form of optical imaging in a brain slice preparation, we found that the corticothalamocortical pathway drove robust activity in higher-order somatosensory cortex. When the direct corticocortical pathway was interrupted, secondary somatosensory cortex showed robust activity in response to stimulation of the barrel field in primary somatosensory cortex (S1BF), which was eliminated after subsequently cutting the somatosensory thalamus, suggesting a highly efficacious corticothalamocortical circuit. Furthermore, after chemically inhibiting the thalamus, activation in secondary somatosensory cortex was eliminated, with a subsequent return after washout. Finally, stimulation of layer 5B in S1BF, and not layer 6, drove corticothalamocortical activation. These findings suggest that the corticothalamocortical circuit is a physiologically viable candidate for information transfer to higher-order cortical areas.

Burst and tonic firing in thalamic cells of unanesthetized, behaving monkeys.

Thalamic relay cells fire in two distinct modes, burst or tonic, and the operative mode is dictated by the inactivation state of low-threshold, voltage-gated, transient (or T-type) Ca2+ channels. Tonic firing is seen when the T channels are inactivated via membrane depolarization, and burst firing is seen when the T channels are activated from a hyperpolarized state. These response modes have very different effects on the relay of information to the cortex. It had been thought that only tonic firing is seen in the awake, alert animal, but recent evidence from several species suggests that bursting may also occur. We have begun to explore this issue in macaque monkeys by recording from thalamic relay cells of unanesthetized, behaving animals. In the lateral geniculate nucleus, the thalamic relay for retinal information, we found that tonic mode dominated responses both during alert behavior as well as during sleep. We nonetheless found burst firing present during the vigilant, waking state. There was, however, considerably more burst mode firing during sleep than wakefulness. Surprisingly, we did not find the bursting during sleep to be rhythmic. We also recorded from relay cells of the somatosensory thalamus. Interestingly, not only did these somatosensory neurons exhibit much more burst mode activity than did geniculate cells, but bursting during sleep was highly rhythmic. It thus appears that the level and nature of relay cell bursting may not be constant across all thalamic nuclei.

Relative distribution of synapses in the A-laminae of the lateral geniculate nucleus of the cat

Previous electron microscopic studies of synaptic terminal distributions in the lateral geniculate nucleus have been flawed by potential sampling biases favoring larger synapses. We have thus re‐investigated this in the geniculate A‐laminae of the cat with an algorithm to correct this sampling bias. We used serial reconstructions with the electron microscope to determine the size of each terminal and synaptic type. We observed that RL (retinal) terminals are largest, F (local, GABAergic, inhibitory) terminals are intermediate in size, and RS (cortical and brainstem) terminals are smallest. We also found that synapses from RL terminals are largest, and thus most oversampled, and we used synaptic size data to correct for sampling errors. Doing so, we found that the relative synaptic percentages overall are 11.7% for RL terminals, 27.5% for F, and 60.8% for RS. Furthermore, we distinguished between relay cells and interneurons with post‐embedding immunocytochemistry for GABA (relay cells are GABA negative and interneurons are GABA positive). Onto relay cells, RL terminals contributed 7.1%, F terminals contributed 30.9%, and RS terminals contributed 62.0%. Onto interneurons, RL terminals contributed 48.7%, F terminals contributed 24.4%, and RS terminals contributed 26.9%. We also found that RL terminals included many more separate synaptic contact zones (9.1 ± 1.6) than did F terminals (2.6 ± 0.2) or RS terminals (1.02 ± 0.02). We used these data plus the calculation of overall percentages of each synaptic type to compute the relative percentage of each terminal type in the neuropil: RL terminals represent 1.8%, F terminals represent 14.5%, and RS terminals represent 83.7%. We argue that this relative synaptic paucity is typical for driver inputs (from retina), whereas modulator inputs (all others) require many more synapses to achieve their function. J. Comp. Neurol. 416:509–520, 2000.

Visual field defects in monocularly and binocularly deprived cats.

Abstract (1) A perimetry test was used to measure the visual responsiveness of discrete regions in the visual field of 2 normal, 4 monocularly deprived (MD) and 2 binocularly deprived (BD) cats. One of the MD cats as an adult underwent a reverse suture operation which forced it to use its formerly deprived eye for a 9 month period. Except for this MD cat which was tested only with its formerly deprived eye, each cat was tested binocularly and monocularly with each eye. (2) In agreement with previous results, normal cats responded binocularly to objects presented anywhere in the region bounded approximately from 100° right-lateral to 100° left-lateral. The monocular visual fields were measured to be approximately from 100° ipsilateral (to the open eye) to 45° contralateral. Thus the binocular segment of visual field includes the region bounded bilaterally by about 45°, and the monocular segment of each side is bounded approximately between 45° and 100°. (3) Each of the 3 MD cats tested with both eyes showed a normal monocular visual field for the non-deprived eye. Each with the deprived eye, however, ignored objects presented in the binocular segment yet, after a period following eye-opening, responded fairly normally to objects presented in the monocular segment. Binocularly, the visual fields of these cats appeared fairly normal. This response pattern was evident during the first testing after opening of the deprived eye although the responses with this eye improved considerably in the ensuing days. (4) The MD cat with reverse suture had a monocular visual field for its formerly deprived eye which closely matched the deprived eye fields of the other 3 MD cats. The reverse suture procedure resulted in no qualitative improvement for the formerly deprived eye. (5) Each BD cat had a fairly normal binocular visual field. When tested monocularly, however, they consistently ignored stimuli presented in the hemifield contralateral to the open eye. Unlike the MD cats, no visual responses were seen in the BD cats for several days after eye-opening. (6) The behavior of MD cats is suggested to be related to physiological deficits which are limited to the binocular segment of the geniculostriate system, and perhaps also to this segment of the superior colliculus. It is further suggested that the behavior of BD cats results from a cortex which is non-functional for visually guided behavior and a superior colliculus which controls this behavior but which receives functional visual afferents almost exclusively from the contraleteral retina.

Dual response modes in lateral geniculate neurons: Mechanisms and functions

Relay cells of the lateral geniculate nucleus, like those of other thalamic nuclei, manifest two distinct response modes, and these represent two very different forms of relay of information to cortex. When relatively hyperpolarized, these relay cells respond with a low threshold Ca 2+ spike that triggers a brief burst of conventional action potentials. These cells switch to tonic mode when depolarized, since the low threshold Ca 2+ spike, being voltage dependent, is inactivated at depolarized levels. In this mode they relay information with much more fidelity. This switch can occur under the influence of afferents from the visual cortex or parabrachial region of the brain stem. It has been previously suggested that the tonic mode is characteristic of the waking state while the burst mode signals an interruption of the geniculate relay during sleep. This review surveys the key properties of these two response modes and discusses the implications of new evidence that the burst mode may also occur in the waking animal.

Development of interocular alignment in cats

Abstract Kittens are born with a large divergent strabismus. Fourteen kittens observed daily from birth concurrently developed both visually guided behavior and normal interocular alignment during the second postnatal month. (Interocular alignment is defined as the angle formed by the visual axes.) Once achieved, this normal interocular alignment is resistant to a number if alterations in the cats visual input. Two cats with adult eyelid closure (one binocular, one monocular), 3 cats with adult unilateral visual cortex ablations, and 3 cats with adult transection of the optic chiasm along the sagittal midline did not develop strabismus. However, all 5 kittens reared with binocular eyelid closure and 9 of 10 reared with monocular eyelid closure developed a stable strabismus. The former all displayed a similar divergent strabismus whereas strabismus in the latter covered a wide range of interocular misalignments. A purely mechanical explanation is discarded sinceboth eyes of cats reared with monocular closure were similarly misaligned. These results indicate that cats require a normal, binocular visual environment during development to achieve the proper interocular alignment. It is hypothesized that during normal development, the binocular patterned visual input stimulates some part or parts of the cats visual system to align the eyes properly. Binocular closure results in no patterned stimulation, so the eyes remain diverged. Monocular closure allows patterned stimulation through the open eye, and this initiates alignment which results in a wide range of errors due to the lack of data from the closed eye. Apparently the visual system does not require the visual cortex for this alignment since 3 kittens reared with extensive visual cortex ablations made during the 8th postnatal day demonstrated the normal development of both visually guided behavior and interocular alignment.